The CLDN16 gene is located on chromosome 3 at 3q28. CLDN16 encodes the renal tight junction protein claudin-16 which participates in the paracellular reabsorption of calcium and magnesium in the thick ascending limb of the loop of Henle (PMID: 18003771).
CLDN16 was first reported in relation to autosomal recessive renal hypomagnesemia, type 3 (OMIM: 248250) in 1999 (Simon et al., PMID: 10390358). The preferred disease name suggested for this disorder is 'autosomal recessive renal hypomagnesemia with hypercalciuria and nephrocalcinosis - CLDN16'. This progressive renal tubular disorder is characterized by excessive urinary losses of calcium and magnesium (PMID: 26613020). The mechanism of pathogenicity is known to be loss of function.
13 variants (9 missense, 1 start-loss, 1 splice, 1 deletion and 1 nonsense) have been reported in nine probands in four publications (PMID: 10390358, 11518780, 18003771, 32869508) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by expression, biochemical function, protein-protein interactions, and an animal model (PMID: 17442678, 10390358, 18188451). A total of 3.5/6 pts. for experimental evidence was reached
In summary, there is definitive evidence supporting the relationship between CLDN16 and autosomal recessive renal hypomagnesemia, type 3 (OMIM: 248250). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date 12/06/2023 (SOP Version 9).
The CLDN16 gene is located on chromosome 3 at 3q28. CLDN16 encodes the renal tight junction protein claudin-16 which participates in the paracellular reabsorption of calcium and magnesium in the thick ascending limb of the loop of Henle (PMID: 18003771).
CLDN16 was first reported in relation to autosomal recessive renal hypomagnesemia, type 3 (OMIM: 248250) in 1999 (Simon et al., PMID: 10390358). The preferred disease name suggested for this disorder is 'autosomal recessive renal hypomagnesemia with hypercalciuria and nephrocalcinosis - CLDN16'. This progressive renal tubular disorder is characterized by excessive urinary losses of calcium and magnesium (PMID: 26613020). The mechanism of pathogenicity is known to be loss of function.
13 variants (9 missense, 1 start-loss, 1 splice, 1 deletion and 1 nonsense) have been reported in nine probands in four publications (PMID: 10390358, 11518780, 18003771, 32869508) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by expression, biochemical function, protein-protein interactions, and an animal model (PMID: 17442678, 10390358, 18188451). A total of 3.5/6 pts. for experimental evidence was reached
In summary, there is definitive evidence supporting the relationship between CLDN16 and autosomal recessive renal hypomagnesemia, type 3 (OMIM: 248250). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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